Approximately 10 million people in the U.S. are estimated to have osteoporosis, a disease that results in over 1.5 million bone fractures a year. It is now known that the accumulation of fat cells (adipocytes) in bone marrow is a major factor contributing to age-related bone loss. Women with osteoporosis have higher numbers of marrow adipocytes than those women with healthy bone, and bone formation rate is inversely correlated with adipocyte number in bone tissue biopsies from both men and women. Our goal is to identify flavonoid compounds from natural sources that inhibit bone marrow adipogenesis and increase the expression of osteogenic factors in bone as a novel strategy for osteoporosis prevention and treatment. We will screen a large number of flavonoids to identify those compounds with potent osteogenic and anti-adipogenic activity using the following specific aims: Specific aim 1 will identify flavonoid compounds that inhibit adipogenesis in a murine preadipocyte (3T3-L1) cell line. Specific aim 2 will identify flavonoid compounds that increase the expression of osteogenic factors in a murine pre-adipocyte (3T3-L1) cell line and a pre-osteoblast murine cell line (MC3T3-E1). In specific aim 3 we will validate the osteogenic and anti-adipogenic potential of the flavonoid compounds identified in the murine cell line screens using ex vivo cultures of human bone marrow aspirates. Phase II of this research will involve testing the efficacy of these compounds in vivo in an animal model, identifying potential synergies between compounds, and validating a novel method of delivering and releasing these compounds into the bone marrow microenvironment.